In multiple sclerosis (MS), there is a preferential loss of myelin- associated glycoprotein (MAG) at the edges of the plaques. Much of the MAG remaining is in the form of dMAG, a proteolytic cleavage product of a myelin-associated, calcium activated neutral protease (calpain). The MAG loss in MS may be related to calpain. dMAG is also present in some patients with AIDS ( see Z01NS02805-06 LMCN). The MAG/dMAG conversion rate in incubated myelin from different species is greatest in human myelin, rapid in other primates, and much slower in mammals such as rodents. This suggests that dMAG formation may be relevant to human demyelinating diseases. The MAG/dMAG conversion rate is very sensitive to the Ca2+ levels in myelin incubations. Purified human calpain incubated with purified human MAG degraded the MAG totally. To determine the native proteolysis site for calpain, dMAG from three species was chemically purified. Peptide fragments of the isolated dMAG were generated enzymatically and the peptide containing the dMAG carboxy terminus was purified by reverse phase HPLC and then sequenced. Biochemical analysis of white matter biopsies from 2 young girls with a progressive leukodystrophy, due to unknown causes, revealed the presence of all the characteristic myelin proteins and lipids at very low levels. Differential display assays were started to elucidate the possible cause of the leukodystrophy. In most hypomyelinating mutant animals, myelin basic protein (MBP) and proteolipid protein (PLP) are decreased more than MAG and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), due to a greater deficiency of compact myelin than of associated oligodendroglial membranes. However a new neurological rat mutant, the TAIEP rat, expresses decreased amounts of MAG compared to other myelin proteins. In the younger mutants MAG has a higher molecular weight than in age-matched controls, most likely due to an extended presence of the immature large isoform of MAG. Total MAG mRNA levels were the same in affected and control rats. PCR of TAIEP samples showed mRNA for both the immature and mature isoforms of MAG. Also in caprine beta-mannosidosis, MAG, CNP and PLP levels were equally decreased, but MBP was relatively spared. The presence of large storage vesicles might interfere with the protein transport of MAG, PLP and CNP, while MBP translation is at the site of insertion into the myelin. The mRNA levels for MAG, PLP and MBP were decreased equally to about 50% supporting this hypothesis.